The principal goal of the proposed research program is to combine a biophysical and biochemical-clinical approach to the study of hemoglobinopathies. The initial studies planned to accomplish this aim involve a newly discovered property of sickle hemoglobin, which is the denaturation of the oxygenated form of the molecule by shaking. The studies will include investigation of the mechanism of denaturation of sickle oxyhemoglobin, the development of new clinical tests based on this property, the study of the significance of intraerythrocytic denaturation of sickle oxyhemoglobin, and the effect of drugs which prevent mechanical denaturation. In addition, studies regarding hemoglobin abnormalities in hemoglobin C disease and thalassemia will be initiated similarly with a biophysical approach. The long-term aims of this research are to provide a better understanding of sickle cell disease and other hemoglobinopathies, and to investigate new methods of therapy for these disorders.